Novel Vaccine Platforms and Combinations最新文献

{"title":"Abstract B105: A cancer vaccine targeting many neoantigens is required for effective eradication of large tumors","authors":"A. D’Alise, G. Leoni, G. Cotugno, F. Troise, F. Langone, Imma Fichera, M. Lucia, Rosa Vitale, Adriano Leuzzi, Veronica Bignone, E. D. Matteo, Fabio Giovanni Tucci, L. Avalle, V. Poli, A. Lahm, M. Catanese, A. Folgori, S. Colloca, A. Nicosia, E. Scarselli","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B105","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B105","url":null,"abstract":"Cancer neoantigens (nAgs) have the potential to elicit strong and tumor-specific immune responses and are, therefore, of great interest for cancer immunotherapeutic strategies, including therapeutic vaccines. Here we developed a novel neoantigen cancer vaccine based on adenoviruses derived from non-human Great Apes (GAds). GAds vaccination was highly effective in prophylactic or early therapeutic treatment of mouse tumors, independently of the number of encoded nAgs. In presence of high tumor burden, GAd has no antitumor effect unless combined with anti-PD1 treatment. In this more stringent setting, effectiveness of vaccination required the targeting of many neoantigens. Analysis of gene expression profile of tumors from responder mice showed greater diversification of the T cell repertoire with increased number of clonotypes in combo treated animals compared to anti-PD-1. Data suggest that GAd vaccines encoding a large number of nAgs can synergize with checkpoint inhibitors therapy by increasing the breadth of nAgs-specific T cells. Citation Format: Anna Morena D9Alise, Guido Leoni, Gabriella Cotugno, Fulvia Troise, Francesca Langone, Imma Fichera, Maria De Lucia, Rosa Vitale, Adriano Leuzzi, Veronica Bignone, Elena Di Matteo, Fabio Giovanni Tucci, Lidia Avalle, Valeria Poli, Armin Lahm, Maria Teresa Catanese, Antonella Folgori, Stefano Colloca, Alfredo Nicosia, Elisa Scarselli. A cancer vaccine targeting many neoantigens is required for effective eradication of large tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B105.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"52 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84485867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B142: Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy","authors":"Qian Yin","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B142","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B142","url":null,"abstract":"While the human immune system is often able to protect the body from infectious pathogens, it has multiple mechanisms to inhibit mounting an immune system against what it perceives as “self” and thus often fails to eliminate cancer cells since they seem to have the characteristics of “self.” Our lab found that cytotoxic CD8+ T-cells that recognize self antigens in the peripheral blood of healthy humans were present in frequencies similar to those specific for non-self antigens, but these self-specific CD8+ T-cells are resistant to activation and/or expansion. We hypothesized that tumor-infiltrating CD8+ T-cells recognizing self antigens are often in an anergized state but they could be activated with the appropriate immunostimulatory signals to augment antitumor immunity. Thus, we developed a poly(lactide-co-glycolide) nanoparticle (PLGA NP) based immunostimulatory platform that is surface-functionalized with monoclonal anti-CD28 antibody (Ab), and encapsulated interleukin-2 (IL-2), toll-like receptor-2 (TLR2) agonist and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the hydrophobic core. This platform enables the encapsulated immunostimulatory drugs to be continuously released in the tumor microenvironment to activate the tumor infiltrating self-specific CD8+ T-cells in order to enhance antitumor immune response while minimizing the rapid diffusion of these drugs into other parts of the body, greatly reducing the systemic toxicities. Our results demonstrated that the mice bearing melanoma or colon cancers treated with the stimulatory PLGA NP have elicited potent T-cell response, resulting in marked tumor regression and increased overall survival. The developed PLGA NPs are also capable of generating an immunologic memory that prevented tumor growth after rechallenging the survivor mice with the same cancer cell type. Moreover, the developed PLGA NPs can be combined with checkpoint blocking antibodies to achieve the synergistic effect, significantly prolonging the overall survival. We also applied the single-cell TCR sequencing technique to assess both T-cell receptor and phenotypic characteristics of tumor-infiltrating CD8+ T-cells after NP stimulation. The result was further combined with yeast-display libraries of peptide-MHC to identify tumor-specific antigens. Citation Format: Qian Yin. Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B142.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82294034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B115: Optimization of cancer vaccine development by using Multiplexed Identification of T-cell Receptor Antigen specificity (MIRA)","authors":"Peter Ebert, M. Klinger, E. Osborne, R. Taniguchi, Joyce K. Hu, Tim Hayes, S. Benzeno, Adria Carbo, Melanie B Laur, Erica L. Eggers, H. Robins","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B115","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B115","url":null,"abstract":"Therapeutic vaccines have been in development for decades with the goal of priming and boosting an immune response against specific antigens in cancer patients. More recently, vaccination with mutation-derived neoantigens has emerged as is an attractive approach to treat cancer patients. However, appropriately selecting immunogenic antigens and neoepitopes that successfully prime the immune system of cancer patents remains a challenge. In fact, despite extensive efforts throughout the years, many vaccines have proven to be ineffective in mediating a clinically relevant anti-tumor immune response in humans. With the advent of emerging new technologies, including the combination of next-generation sequencing and improved bioinformatics tools, a new era of vaccine development is underway. Hereto, we present a novel, highly sensitive, multiplex approach, known as Multiplexed Identification of T-cell Receptor Antigen specificity (MIRA), that combines high-throughput TCR repertoire sequencing with conventional immune monitoring techniques to assess T-cell specificity to large numbers of query antigens. MIRA maps antigen specificity to TCR sequence at an unprecedented sensitivity (1 in ~10 million T-cells) and scale (more than 400 antigens at a time). To validate this approach, we assessed the response of more than 10 million naive human T-cells from each of 50 healthy donors against a panel of 366 neoepitopes. These include post-translationally modified peptides, derived from over 130 prevalent mutations in greater than 50 cancer indications. From three billion total input T-cells, we identified tens of thousands of TCRB sequences from responsive T-cell clones, of which at least one TCR was yielded for the majority of queried neoepitopes. The TCRs identified were skewed toward a small number of query antigens, with 12 neoepitopes accounting for over 50% of the TCRs identified. This suggests a higher precursor frequency of specific T-cells in the naive repertoire or a higher immunogenicity of these epitopes or both. By performing MIRA experiments in parallel using transgenes versus peptides, we can further validate which of the neoepitopes were also presented via cells’ natural antigen presentation machinery. Of note, we also paired 52% of the TCRB sequences with their cognate TCRA subunit sequence thus permitting reconstitution of individual TCRs. Generating immunogenicity data to antigens of interest at scale facilitates an opportunity to better inform antigen selection in vaccine programs and improve vaccine design. Once a vaccine has been designed and administered to a patient, MIRA offers a unique solution to assess peptides based on their ability to elicit robust T responses. By creating a post-vaccination, patient-specific MIRA, a permanent record or signature of that patient’s response to the vaccine is created. This information can then be leveraged to identify early biomarkers of response to the vaccine and monitor this response longitudinally","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80836627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B141: Anti-tumor immune responses elicited by mesothelin virus-like particles vaccine effectively controls pancreatic cancer in animal models","authors":"Q. Yao, Ethen Poteet, Zhengdong Liang, Phoebe Lewis, Zhiyin Yu, Changyi J. Chen","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B141","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B141","url":null,"abstract":"Pancreatic cancer is the 12th most common cancer, but is the 3rd leading cause of cancer death in America. This disparity is directly related to three factors: the difficulty in early detection of the disease, pancreatic cancer’s resistance to chemotherapy, and a tendency for the cancer to metastasize early and quickly. Here, we propose a novel immunotherapy to bypass pancreatic cancer’s resistance to standard chemotherapy. We have developed a virus-like particle (VLP) based on an HIV backbone Gag and pancreatic cancer-associated protein mesothelin (MSLN). Vaccination of C57BL/6 mice with MSLN VLP can efficiently activate the immune system and reduce and in some cases eliminate the host’s pancreatic cancer. Our results show that MSLN VLPs induce both humoral and cytotoxic specific response against MSLN in mouse pancreatic cancer models. Specifically, after vaccination with MSLN VLPs, significant increases in CD8+ MSLN specific T-cells and increases in serum anti-MSLN IgG were detected. Furthermore, we observed an increase in the serum of pro-inflammatory cytokine IFN-γ and B cell stimulator IL-5. Consistent with the increased IL-5, we observed a significant increase in tumor infiltrating B cells in the MSLN VLP immunized groups, but neither Gag VLP control nor unimmunized mice. Furthermore, while all tumor-bearing mice generated some antibodies towards MSLN, our MSLN VLP immunized mice had significantly higher serum titers of IgG1, IgG2B, and IgG3. Both Gag VLP and MSLN VLP immunized mice had a decreased tumor volume compared to control, but passive transfer of sera only from MSLN VLP immunized mice decreased tumor volume and increased survival of unimmunized tumor bearing mice, while Gag VLP immunized mice had much less effect. Overall, we have developed a promising vaccine for pancreatic cancer warranting additional studies with adjuvants and combination treatments with standard-of-care chemotherapy. Citation Format: Qizhi Cathy Yao, Ethen Poteet, Zhengdong Liang, Phoebe Lewis, Zhiyin Yu, Changyi Chen. Anti-tumor immune responses elicited by mesothelin virus-like particles vaccine effectively controls pancreatic cancer in animal models [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B141.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"71 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75863637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B118: Development of a novel prostatic acid phosphatase-derived vaccine for the treatment of advanced prostate cancer","authors":"P. Vu, J. Vadakekolathu, D. Christensen, L. Durrant, G. Pockley, S. McArdle","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B118","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B118","url":null,"abstract":"Our aim is to develop a new and more effective prostatic acid phosphatase (PAP) peptide-based vaccine for the treatment of advanced prostate cancer (PCa). We have previously shown that a 15mer PAP peptide-derived vaccine, when administered as a DNA vaccine, could induce PAP-specific T-cell responses and reduce the growth of implanted murine TRAMP C1-derived tumors in a syngeneic heterotopic murine model. We have subsequently developed an elongated (42mer) PAP-derived peptide in which Alanine at position 115 was replaced by Leucine.Herein, the capacity of the wild-type and mutated PAP-42mer vaccines to induce PAP-specific immune responses were compared in two pre-clinical murine models. The murine PAP-42mer sequence was evaluated in C57Bl/6 mice and the human PAP-42mer sequence in HHDII/DR1 transgenic mice. Following the identification of the most promising PAP-42mer sequence, the capacities of different delivery systems (CpG adjuvant, CAF09 adjuvant and ImmunoBody® DNA vaccine) to generate PAP-specific immunity were compared. For these studies, the responsiveness of splenocytes isolated from immunized mice following in vitro stimulation with MHC class I or class II wild-type vaccine-derived peptides (8/9 or 15 amino-acid long) was assessed using an IFNγ ELISpot assay and by immunophenotyping of splenic T-cells using flow cytometry. The ability of splenocytes to kill relevant targeT-cells after a short in vitro stimulation was assessed using a 51chromium release assay. B16 cells that had been knocked out for beta-2m gene and transfected to express chimeric HLA-A2 (HHDII), HLA-DR1 and human PAP implanted into HHDII/DR1 mice was used as a proof-of-concept model to assess the antitumor efficacy of the hPAP42mer mutated vaccine with CAF09 adjuvant in a prophylactic setting.The mutated murine and human PAP42mer-based vaccines induced a higher number of IFNγ-releasing splenocytes in response to in vitro stimulation with class I or class II vaccine-derived peptides and generated cells having a higher functional avidity. CAF09 and ImmunoBody® were superior to CpG in inducing PAP-specific immune responses, with CAF09 eliciting strong immune responses in both models, and ImmunoBody® eliciting potent immune responses in C57Bl/6 mice. Indeed, a higher proportion of CD8+ T-cells were able to release IFNγ and TNFα, to proliferate (Ki67 expression) and to degranulate (CD107a and Granzyme B expression) after short incubation with MHC class-I peptide. These vaccines strategies were also able to induce a higher proportion of memory CD8+ T-cells and the expression of PD-1 on CD8+ T-cells. Additionally, splenocytes from vaccinated mice were able to kill MHC class I peptide-pulsed targeT-cells (T2 and RMAS cells) and murine PCa cells expressing PAP (TRAMP-C1 cells) in vitro. The vaccine slowed the growth of human-PAP+-B16-derived tumors in HHDII/DR1 model and prolonged the survival (9 days delay for 30% of the mice). Splenic CD8+ T-cells and CD8+ tumor-infiltrating ce","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90558600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B112: Combined therapy with an autologous tumor cells/bacillus Calmette-Guérin/formalin-based vaccine plus anti-PD-1 inhibitor enhances the antitumor response in a 4T1 breast cancer model","authors":"Maria Jose Godoy Calderon, Eglys González Marcano, A. Convit","doi":"10.1158/2326-6074.cricimteatiaacr18-b112","DOIUrl":"https://doi.org/10.1158/2326-6074.cricimteatiaacr18-b112","url":null,"abstract":"Immune checkpoint inhibitors have shown satisfactory results in different types of cancer, such as lung cancer and melanoma. However, in breast cancer their benefit as a stand-alone treatment have not been robust, suggesting the need of combined therapies. In preclinical and clinical studies some checkpoint inhibitors have shown enhancement of cancer vaccines’ antitumor effects. Cancer vaccines represent a promising immunotherapy since they induce a specific long-term immune response against tumor antigens, leading to an effective tumor elimination with minimal side effects. Based on successful previous experiences using an autologous tumor cells/bacillus Calmette-Guerin (BCG)/formalin-based vaccine in breast cancer, we aimed to enhance its antitumor properties by combining it with anti-PD-1. We used a 4T1 breast cancer model in BALB/c mice, receiving four weekly injections of either Phosphate Buffered Saline (G1), 50 μg anti-PD-1 (G2), or the vaccine plus anti-PD-1 (200 µg autologous tumor cells, 0.0625 mg BCG, 0.02% formalin plus 50 μg anti-PD-1) (G3). In G3, the tumor arrest ability of anti-PD-1 was enhanced, showing a stronger antitumor response compared to G2. This response was characterized by a high infiltration of CD8+ T and PD-1+ cells, and a likely prevalence of CD4+ Th1 cells as suggested by a low T CD4/CD8 ratio. This led to a marked tumor elimination represented by nearly 70% of tumor necrosis, and a 3-fold reduction of both tumor volume and mitotic index. Interestingly, anti-PD1 seemed to successfully enhance an important part of the vaccine’s antitumor response, indicated by 50% less TAMs infiltration and 10% more necrosis, though not significantly improving the overall antitumor effect of the vaccine. These limitations of the combined therapy may be overcome by using a higher anti-PD-1 dose and administering the two treatments at different times. Furthermore, the positive and promising effects of applying both treatments individually and combined, plus the vaccine’s low-cost and simple preparation method, encourage us to continue this study. The vaccine should be evaluated in combination with other checkpoint inhibitors and/or other target-specific compounds that can lead to new, highly effective, less toxic, personalized breast cancer immunotherapies. Citation Format: Maria Jose Godoy Calderon, Eglys Gonzalez Marcano, Ana Federica Convit. Combined therapy with an autologous tumor cells/bacillus Calmette-Guerin/formalin-based vaccine plus anti-PD-1 inhibitor enhances the antitumor response in a 4T1 breast cancer model [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B112.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89330145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B128: Timing and sequence of CpG and anti-OX40 is critical for in situ vaccination","authors":"Idit Sagiv-Barfi, D. Czerwinski, R. Levy","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B128","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B128","url":null,"abstract":"Immunotherapy seeks to enhance or manipulate host antitumor immunity by various approaches, among them, in situ vaccination. In situ vaccination is a local intervention in which immune enhancing agents are injected locally into one site of tumor, triggering a T-cell immune response locally that then travels to attack cancer throughout the body. We have employed a preclinical strategy whereby the same syngeneic tumor is implanted at two separate sites in the body. One tumor is then injected with the test agents and the resulting systemic immune response, if any, is detected by the regression of the distant, untreated tumor. In this test for abscopal therapeutic effects, the combination of unmethylated CG-enriched oligodeoxynucleotide (CpG)—a TLR9 ligand—and agonist anti-OX40 antibody has provided the most impressive results. This combination lead to durable disease control and long-term treatment-free survival in multiple mouse models of cancer. CpG induced myeloid cells to secrete cytokines, which subsequently induced OX40 expression on T-cells. Thus, we hypothesized that administration sequence and timing may affect the antitumor responses of in situ vaccination. In order to screen for the best sequence and timing we implanted A20 lymphoma tumors bilaterally in opposite sides of the abdomen of Balb/C mice. After tumors were established, one tumor was injected at the selected sequence and timing with the test agents and the resulting immune response was monitored by the measuring growth of the distant, untreated tumor. The systemic antitumor response required the presence of both CD4+ and CD8+ T-cells, as mice treated with the corresponding depleting antibodies were unable to control tumor growth. Even a single injection of low-dose CpG (50µg) and anti-OX40 (8µg) resulted in a fully protective systemic immune response. In addition, the cured animals were protected from rechallenge with the same A20 tumor but not unrelated tumors. Decreasing the dose even further to 10µg CpG and 1µg anti-OX40 partially preserved the therapeutic response with a long-term survival of 60%. Concurrent administration of CpG and anti-OX40 resulted in eradication of both local and distant disease. Sequential administration of CpG followed by anti-OX40 preserved the therapeutic efficacy. However, sequential administration of anti-OX40 followed by CpG significantly attenuated the therapeutic effect. While CpG followed by a 24- or 48-hour-delayed anti-OX40 treatment preserved the therapeutic efficacy of concurrent therapy, 72h delay in anti-OX40 administration resulted in reduced therapeutic effect. These data demonstrate the importance of the administration sequence for fully protective and curative antitumor immune responses. Our data suggest that the anti-OX40 antibody should be administered at the same time as CpG or somewhat delayed but not the other way around. The combination of anti-OX40 and CpG is currently studied in a phase I trial. Our results here impact the pl","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88418438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B125: Targeting human CD141+ DC using CLEC9A antibodies for cancer immunotherapy","authors":"K. Radford, F. E. Pearson, Kelly‐Anne Masterman, Kirsteen M. Tullett, O. Haigh, C. Walpole, Ghazal Daraj, I. L. Rojas, M. Lahoud","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B125","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B125","url":null,"abstract":"Dendritic cells (DC) are a heterogeneous cell population, with specialist subtypes driving specific immune responses. In mice, the cDC1 subset (also referred to as Batf3-dependent DC, XCR1+ DC, CD8+ DC in lymphoid tissues and CD103+ DC in peripheral tissues) is essential for the induction of tumor immune responses and for the efficacy of checkpoint inhibitor blockade and adoptive T-cell immunotherapies. Vaccines that can deliver antigens (Ag) directly to DCs in vivo are more effective than cell-based therapies in mouse models and are promising approaches to translate to humans. CD141+ DC are the human cDC1 equivalent and specifically express the C-type lectin-like receptor CLEC9A, that facilitates cross-presentation of dead cell Ag. Targeting tumor-associated Ag (TAA) to human CD141+ DC using CLEC9A antibody (Ab) is therefore an attractive strategy to induce or boost tumor immune responses. NYESO1 and WT1 are well characterised, highly immunogenic TAA expressed by a broad array of tumor types. We developed recombinant human chimeric IgG4 Ab specific for human CLEC9A genetically fused to NYESO1 or WT1. For comparison we developed TAA fusions with chimeric IgG4 Ab specific for human DEC-205, which is expressed by many human leukocytes, and β-galactosidase as an irrelevant isotype control. CLEC9A-NYESO1 and CLEC9A-WT1 Abs retained their binding specificity for CD141+ DC. Following uptake of CLEC9A-WT1, CD141+ DC cross-presented a WT-1 HLA-A24-restricted epitope for recognition by specific CD8+ cytotoxic T-cells. Likewise, a HLA-A2-restricted NYESO1 epitope was cross-presented Ag specific CD8+ T-cells by CD141+ DC following uptake of CLEC9A-NYESO1. For both TAA, the CLEC9A Abs were more efficient at delivery of Ag for cross-presentation than DEC-205 or isotype control Abs. Moreover, using a humanized mouse model in which functional human CD141+ DC and Ag-specific T-cells develop, CLEC9A-TAA Ab induced priming of Ag-specific T-cells. Our data advocate further development of human CLEC9A targeting Abs as cancer vaccines. Citation Format: Kristen Radford, Frances Pearson, Kelly-Anne Masterman, Kirsteen Tullett, Oscar Haigh, Carina Walpole, Ghazal Daraj, Ingrid Leal Rojas, Mireille Lahoud. Targeting human CD141+ DC using CLEC9A antibodies for cancer immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B125.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"123 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89441427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract IA25: Targeting tumor neoantigens to drive effective tumor immunity","authors":"Catherine J. Wu","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-IA25","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-IA25","url":null,"abstract":"With the recent availability of novel immunologic agents, priority has shifted to understanding the mechanisms of and predicting responses to each treatment. At the heart of cancer and host immune cell interactions is the tumor antigen and host antigen-specific T cell interaction, with the cytotoxic T cell-cognate antigen interaction forming the mechanistic basis for immune-mediated recognition and the killing of malignant cells. While the search for immunogenic tumor antigens has been the subject of decades-long studies, multiple lines of evidence have convincingly demonstrated tumor neoantigens as an important class of immunogenic tumor antigens. Neoantigens arise from amino acid changes encoded by somatic mutations in the tumor cell and have the potential to bind to and be presented by personal HLA molecules. Using next-generation sequencing approaches, we can now systematically identify mutations leading to amino acid changes that can be potentially recognized immunologically through the implementation of neoantigen discovery pipelines. In recent studies, we have demonstrated that neoantigens can be safely and feasibly targeted to generate customized cancer vaccines. We have been undertaking pilot clinical trials to develop personal cancer vaccines in melanoma and glioblastoma that utilize synthetic long peptides as delivery approach for this therapy. Recent results and new directions will be discussed. Citation Format: Catherine J. Wu. Targeting tumor neoantigens to drive effective tumor immunity [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA25.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79877684","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Abstract B117: Allogeneic tumor-lysate loaded dendritic cells induce anti-tumor immunity and tumor responses in pre-clinical models of pancreatic adenocarcinoma: Towards clinical trials","authors":"S. P. Lau, Priscilla Kinderman, Melanie Lukkes, Floris Dammeijer, H. Vroman, M. Nimwegen, T. V. Hall, S. H. Burg, J. Aerts, N. Montfoort, C. V. Eijck","doi":"10.1158/2326-6074.CRICIMTEATIAACR18-B117","DOIUrl":"https://doi.org/10.1158/2326-6074.CRICIMTEATIAACR18-B117","url":null,"abstract":"Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Pancreatic cancer has been characterized as a non-cytotoxic T-cell infiltrated tumor, and this may explain the low response rate of immune checkpoint antibodies. A highly immunosuppressive tumor microenvironment and dense desmoplastic stroma in established pancreatic tumors are considered to be the main reasons. Dendritic cells (DCs) are the most potent activators of the immune system and DC vaccination have been shown to successfully induce immune responses in various non-immunogenic malignancies. DCs loaded with an allogeneic mesothelioma tumor cell lysate has proven to be safe, feasible and clinically active in mesothelioma patients. Mesothelioma and pancreatic cancer share tumor characteristics and tumor antigens. We therefore argue that this off-the-shelf vaccine may be beneficial for the treatment of pancreatic cancer. In a murine model we assessed the effectiveness of mesothelioma-lysate loaded DCs against pancreatic adenocarcinoma. C57BL/6 mice were vaccinated with bone-marrow derived DCs both prior to and subsequent to inoculation with subcutaneous syngeneic pancreatic tumor cells (KPC3). DCs were generated with a GM-CSF bone marrow culture and stimulated overnight with CpG along with either pancreatic (KPC3) or mesothelioma tumor (AE17) lysate. Lysates were generated by freeze-thawing and sonification. Mice were challenged with KPC3 tumors and tumor sizes were monitored over time. Immune responses were determined by flow-cytometry of cells in peripheral blood, spleen and tumor. Tumor-specific T-cell responses were investigated by co-culturing purified splenic CD8+ T-cells with IFNg-treated pancreatic cancer cells. DC vaccination preceding tumor challenge led to a significant increase of systemic CD4+ and CD8+ T-cells frequencies in treated mice compared to untreated mice and were persistent over time (p Citation Format: Sai Ping S. Lau, Priscilla P. Kinderman, Melanie M. Lukkes, Floris F. Dammeijer, Heleen H. Vroman, Menno M. van Nimwegen, Thorbald T. van Hall, Sjoerd S.H. van der Burg, Joachim J.G.J.V. Aerts, Nadine A.G. Pronk-van Montfoort, Casper C.H.J. van Eijck. Allogeneic tumor-lysate loaded dendritic cells induce anti-tumor immunity and tumor responses in pre-clinical models of pancreatic adenocarcinoma: Towards clinical trials [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr B117.","PeriodicalId":19329,"journal":{"name":"Novel Vaccine Platforms and Combinations","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88909175","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}